Polymorphic form xvi of fexofenadine hydrochloride

ABSTRACT

Provided is a crystalline (polymorphic) form of fexofenadine hydrochloride, denominated fexofenadine hydrochloride Form XVI.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of prior application U.S. Ser. No.11/243,496 filed Oct. 3, 2005 which is a continuation of priorapplication U.S. Ser. No. 10/459,688, filed Jun. 10, 2003, which claimsthe benefit under 35 U.S.C. § 119(e) of provisional application Ser. No.60/387,972, filed Jun. 10, 2002, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to the solid state chemistry offexofenadine hydrochloride and its use as an active pharmaceuticalagent.

BACKGROUND OF THE INVENTION

4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid of formula (I) (fexofenadine) is an H₁ receptor antagonist and auseful antihistaminic drug. It has low permeability into central nervoussystem tissues and weak antimuscarinic activity, causing it to have fewsystemic side effects.

The antihistamic activity of fexofenadine is disclosed in U.S. Pat. No.4,254,129, incorporated herein by reference. According to the '129patent, fexofenadine can be prepared starting from ethylα,α-dimethylphenyl acetate and 4-chlorobutyroyl chloride, which arereacted under Freidel-Crafts conditions. Chloride is displaced from theFreidel-Crafts product with α,α-diphenyl-4-piperidinemethanol to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,which is isolated as its hydrochloride salt. The ketone is then reducedwith PtO/H₂ and the ester group is hydrolyzed to yield fexofenadinehydrochloride.

Other methods of preparing fexofenadine are discussed in U.S. Pat. Nos.5,578,610, 5,589,487, 5,581,011, 5,663,412, 5,750,703, 5,994,549,5,618,940, 5,631,375, 5,644,061, 5,650,516, 5,652,370, 5,654,433,5,663,353, 5,675,009, 5,375,693 and 6,147,216.

The present invention relates to the solid state physical properties,i.e., polymorphism, of fexofenadine hydrochloride. These properties maybe influenced by controlling the conditions under which fexofenadinehydrochloride is obtained in solid form. Solid state physical propertiesinclude, for example, the flowability of the milled solid. Flowabilityaffects the ease with which the material is handled during processinginto a pharmaceutical product. When particles of the powdered compounddo not flow past each other easily, a formulation specialist must takethat fact into account when developing a tablet or capsule formulation,which may necessitate the use of glidants such as colloidal silicondioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid may have therapeuticconsequences because it imposes an upper limit on the rate at which anorally-administered active ingredient may reach the bloodstream. Therate of dissolution is also a consideration in formulating syrups,elixirs and other liquid medicaments. The solid state form of a compoundmay also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. The polymorphicform may give rise to thermal behavior different from that of theamorphous material or another polymorphic form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetry (DSC), and may be used to distinguish some polymorphic formsfrom others. A particular polymorphic form may also give rise todistinct properties that may be detectable by powder X-ray diffraction,solid state 13C NMR spectrometry and infrared spectrometry.

U.S. Pat. Nos. 5,738,872, 5,932,247 and 5,855,912, incorporated hereinby reference, describe four crystal forms of fexofenadine hydrochloridewhich are designated Forms I-IV. According to the □872 and relatedpatents, Forms II and IV are hydrates and Forms I and III areanhydrates. Each form is characterized by its melting point, onset ofendotherm in the DSC profile, and PXRD. Form I is reported to have acapillary melting point range of 196-201° C., a DSC endotherm with onsetbetween 195-199° C. and a powder X-ray diffraction (“PXRD”) pattern withd-spacings of 14.89, 11.85, 7.30, 6.28, 5.91, 5.55, 5.05, 4.96, 4.85,4.57, 4.45, 3.94, 3.89, 3.84, 3.78, 3.72, 3.63, 3.07, 3.04, 2.45 Å. FormII is reported to have a capillary melting point range of 100-105° C., aDSC endotherm with onset between 124-126° C. and a PXRD pattern withd-spacings of 7.8, 6.4, 5.2, 4.9, 4.7, 4.4, 4.2, 4.1, 3.7, 3.6, 3.5 Å.Form III is reported to have a capillary melting point range of 166-171°C., a DSC endotherm with onset at 166° C. and a PXRD pattern withd-spacings of 8.95, 4.99, 4.88, 4.75, 4.57, 4.47, 4.46, 3.67, 3.65 Å. InExample 2, Form IV is reported to undergo decomposition at 115-116° C.In the general written description, a DSC endotherm with onset at 146°C. is reported. Form IV is reported as having a PXRD pattern withd-spacings of 10.38, 6.97, 6.41, 5.55, 5.32, 5.23, 5.11, 4.98, 4.64,4.32, 4.28, 4.12, 4.02, 3.83, 3.65, 3.51, 3.46 and 2.83 Å.

The '872 patent discusses methods of interconverting Forms I-IV. Aqueousrecrystallization of Form I can be used to produce Form II.Water-minimizing recrystallization or azeotropic distillation of eitherForm II or Form IV can yield Form I. Form III is reported to beaccessible by water minimizing recrystallization of Form II. Crystaldigestion of Form III can be used to obtain Form I. Forms II and IV canbe obtained directly by sodium borohydride reduction of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetateas described in Examples 1 and 2.

International Publication No. WO 00/71124 A1, discloses that amorphousfexofenadine hydrochloride can be prepared by lyophilizing or spraydrying a solution of fexofenadine hydrochloride. The product ischaracterized by its IR spectrum and a featureless PXRD pattern.

International Publication Nos. WO 01/94313 and WO 02/066429 are alsodirected to polymorphic forms of fexofenadine hydrochloride.

Fexofenadine hydrochloride Forms V, VI, and VIII through XV aredisclosed in US 20030021849 and US 20020177608 (WO02/080857), both ofwhich are incorporated herein by reference.

There is a need in the art for additional polymorphic forms offexofenadine hydrochloride.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a crystalline fexofenadinehydrochloride in the solid state characterized by data selected from thegroup consisting of: a PXRD pattern with peaks at 10.1, 15.2, 18.6,19.2, 20.1±0.2 degrees two theta; a DSC profile with two endothermicpeaks at a temperature range of up to about 125° C. and an additionalendotherm at a temperature of about 135° C.; and a TGA thermogram with aloss on drying (LOD) of about 6% to about 10% at a temperature range ofup to about 145° C.

In another aspect, the present invention provides pharmaceuticalformulations of fexofenadine hydrochloride Form XVI and their methods ofadministration.

In another aspect, the present invention provides a process forpreparing crystalline fexofenadine hydrochloride Form XVI comprising thesteps of combining fexofenadine free base, HCl and methanol to obtain asolution, precipitating fexofenadine hydrochloride in the presence ofmethanol and recovering the fexofenadine hydrochloride.

In another aspect, the present invention provides a process forpreparing crystalline fexofenadine hydrochloride Form XVI comprising thesteps of combining fexofenadine base, HCl and methanol to obtain asolution, evaporating the methanol to obtain a residue, adding methanoland a C₅ to C₁₂ hydrocarbon to the residue to precipitate fexofenadinehydrochloride and recovering the fexofenadine hydrochloride.

In another aspect, the present invention provides a process forpreparing crystalline fexofenadine hydrochloride Form XVI comprising thesteps of combining a solution of HCl in a mixture of methanol andisopropyl alcohol, with fexofenadine base, to obtain a solution,evaporating the methanol and the isopropyl alcohol to obtain a residue,adding a mixture of methanol and heptane to the residue to precipitatecrystalline fexofenadine hydrochloride and recovering the fexofenadinehydrochloride.

In another aspect, the present invention provides a process forpreparing crystalline fexofenadine hydrochloride Form XVI comprising thesteps of combining fexofenadine free base, HCl and methanol to obtain asolution, removing the methanol to concentrate the solution, seeding thesolution with fexofenadine hydrochloride Form XVI, stirring thesolution, cooling the solution and recovering the fexofenadinehydrochloride.

In another aspect, the present invention provides a process forpreparing fexofenadine hydrochloride Form XVI comprising the step ofstirring a slurry of fexofenadine hydrochloride amorphous in methanolfor a sufficient time to obtain fexofenadine hydrochloride Form XVI.

In another aspect, the present invention provides for a crystalline formof fexofenadine hydrochloride characterized by a PXRD pattern with peaksat 10.1, 15.2, 18.6, 19.2, 20.1±0.2, wherein the crystalline form has awater content of from about 6% to about 10%.

In another aspect, the present invention provides for a crystalline formof fexofenadine hydrochloride characterized by a PXRD pattern with peaksat 10.1, 15.2, 18.6, 19.2, 20.1±0.2, wherein the crystalline form withsaid PXRD peaks is substantially stable under storage at relativehumidity of about 100% for at least about 1 week, and storage at about40° C. and about a 75% relative humidity for at least about 6 months.

In another aspect, the present invention provides for a process forpreparing a crystalline form of fexofenadine hydrochloride having a PXRDpattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1±0.2, comprising thesteps of crystallizing the crystalline form with said PXRD peaks from asolution of fexofenadine hydrochloride in methanol and recovering thecrystalline form.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a PXRD pattern for fexofenadine hydrochloride Form XVI.

FIG. 2 is DSC thermogram for fexofenadine hydrochloride Form XVI.

FIG. 3 is a TGA thermogram for fexofenadine hydrochloride Form XVI.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “MTBE” refers to methyl t-butyl ether (syn. t-butylmethyl ether).

In one aspect the present invention provides for fexofenadinehydrochloride Form XVI. Fexofenadine hydrochloride Form XVI ischaracterized by a PXRD pattern (FIG. 1) with peaks at 5.2, 10.1, 15.2,15.5, 17.0, 17.3, 18.6, 19.2, 19.6, 20.1, 21.7, 22.5, 23.2, 24.0, 24.3,25.6±0.2 degrees two theta. The most characteristic peaks are at 10.1,15.2, 18.6, 19.2, 20.1±0.2 degrees two theta.

Fexofenadine hydrochloride Form XVI is also characterized by a DSCthermogram (FIG. 2) with two large endothermic peaks at a temperaturerange of up to about 125° C. and an additional small endotherm at atemperature of about 135° C. The first endothermic peak (≈75-85 J/g) isobserved at a temperature of about 67° C., while the second endothermicpeak (≈60 J/g) is observed at a temperature of about 120° C., and thethird endothermic peak (≈0.3-2 J/g) is observed at a temperature ofabout 135° C.

The TGA thermogram of fexofenadine HCl Form XVI shows an LOD value ofabout 6% to about 10% in a temperature range of up to 145° C.

Karl Fischer and elemental analysis of fexofenadine hydrochloride FormXVI point to a water content higher than an anhydrate. Fexofenadinehydrochloride Form XVI contains from about 6% to about 10% water byweight as measured by the Karl Fischer method. At the end ofprecipitation step, usually a Form XVI contains about 6% water by KF.But the form absorbs water, and its water content may increase to asmuch as 10% water by weight.

Fexofenadine hydrochloride Form XVI is substantially stable duringstorage. Fexofenadine hydrochloride Form XVI is stable againsttransformation to other crystalline forms upon storage at relativehumidity of up to about 100% for at least about 1 week, and storage atabout 40° C. and about 75% relative humidity for at least about 6months. The conversion is preferably less than about 5%, more preferablyless than about 2% by weight.

In another aspect, the present invention provides for processes forpreparation of fexofenadine hydrochloride Form XVI, which allowpreparing fexofenadine HCl form XVI substantially free of otherpolymorphic forms of fexofenadine HCl, including amorphous form. As usedherein, “substantially free” refers to less than about 5% on a weightbasis, preferably less than about 2%, weight of polymorphic forms otherthan Form XVI compared to the weight of all the polymorphic forms,including Form XVI. A suitable method for determining the presence ofother polymorphic forms is with X-Ray Powder diffraction.

In another aspect, the present invention provides for preparation offexofenadine hydrochloride Form XVI by precipitation of the crystallineform from a methanol containing mixture. In the first step, a solutionof fexofenadine hydrochloride in methanol is prepared. Subsequently,fexofenadine hydrochloride Form XVI may be recovered in various manners,such as by precipitation from the solution (including concentration ofthe solution before precipitation); or removal of the methanol to obtaina residue, followed by precipitation from methanol, or precipitationfrom a mixture of methanol and an anti-solvent. Precipitation may becarried out from both a slurry and a solution. When a residue is addedto methanol, with or without an anti-solvent, generally a slurry isobtained.

In one embodiment, the present invention provides a process forpreparing crystalline fexofenadine hydrochloride Form XVI comprisingcombining fexofenadine free base, HCl and methanol to obtain a solution,precipitating fexofenadine hydrochloride Form XVI from the solution, andrecovering the fexofenadine hydrochloride Form XVI.

In another embodiment, the present invention provides a process forpreparing the crystalline fexofenadine hydrochloride Form XVI comprisingthe steps of combining fexofenadine free base with HCl to obtain asolution in methanol, removing the methanol to obtain a residue, addingmethanol and a C₅ to a C₁₂ hydrocarbon to the residue to causeprecipitation of fexofenadine hydrochloride and recovering thefexofenadine hydrochloride. The addition of an anti-solvent such as a C₅to a C₁₂ hydrocarbon is optional, i.e., the residue may only be taken upin methanol.

In one embodiment, a solution of HCl in a mixture of methanol and apolar organic solvent is added to fexofenadine base, preferably at atemperature of about 0 to about 10° C. An ice bath can be used to coolthe solution. The resulting solution can be filtered to removeimpurities, including any material that does not go into solution.

Suitable polar organic solvents are protic and aprotic polar solventssuch as alcohols, ketones, esters and ethers. Preferred solvents includeacetone and isopropanol. Preferably, a small amount of the polar solventrelative to methanol is used.

The solvent is then removed to obtain a residue. Preferably, the solventis removed by evaporation, more preferably under reduced pressure. Thetemperature can be increased or the pressure reduced to accelerate theevaporation process. Preferably the pressure is reduced by an oil pumpto remove the solvent by evaporation.

Fexofenadine hydrochloride Form XVI is then crystallized from methanol,or a mixture of methanol and a suitable anti-solvent, such as a C₅ to aC₁₂ saturated or a monoaromatic hydrocarbon. Examples of suchhydrocarbons include heptane and hexane, with saturated hydrocarbonssuch as heptane being more preferred. Preferably the ratio of methanolto the hydrocarbon is from about 1:3 to about 1:33 (v/v). Preferably,the resulting mixture is stirred.

The fexofenadine hydrochloride so recovered is then preferably dried ata temperature of about 50° C. to about 80° C., more preferably at atemperature of from about 60° C. to about 70° C., most preferable underreduced pressure. Both the wet and the dried samples are fexofenadinehydrochloride Form XVI.

In another embodiment, fexofenadine hydrochloride Form XVI is preparedby concentrating the solution of fexofenadine hydrochloride in methanolbefore precipitation, preferably followed by seeding and cooling toprecipitate Form XVI. In this embodiment, the solution is preferablyconcentrated to a level of about 2 to about 2.5 volumes of methanol incomparison to the weight of fexofenadine base (ml/g). The fexofenadineHCl methanol solution may optionally be filtered in order to removeforeign particles.

In a preferred embodiment, after the seeding step, the solution isstirred and cooled to enhance precipitation. After precipitation, theresulting suspension may optionally be stirred, preferably at a lowtemperature (about minus 15° C. to about 10° C.) for a sufficient amountof time, preferably for at least about 20 minutes, to increase theyield.

The fexofenadine hydrochloride so recovered is then preferably dried ata temperature of about 50° C. to about 80° C., more preferably at atemperature of from about 60° C. to about 70° C., most preferable underreduced pressure. Both the wet and the dried samples are fexofenadinehydrochloride Form XVI.

In another embodiment, the present invention provides for preparationfexofenadine hydrochloride Form XVI through stirring a slurry ofamorphous fexofenadine hydrochloride in methanol. An anti-solvent mayoptionally be added to the methanol.

In one embodiment, the anti-solvent is a C₅ to C₁₂ hydrocarbon, morepreferably a saturated hydrocarbon and most preferably heptane.Preferably a small amount of methanol compared to heptane is used, morepreferably from about 3% to about 26% volume of methanol compared tovolume of heptane. The slurry process is carried out for a sufficienttime to obtain fexofenadine hydrochloride Form XVI. Preferably theslurry process is carried out for at least about 5 hours, morepreferably from at least about 10 hours and most preferably for at leastabout 15 hours.

One skilled in the art would appreciate that the polymorphs of thepresent invention can be selectively obtained from fexofenadinehydrochloride generally through crystallization with differentrecrystallization solvent systems. The starting material can beanhydrous fexofenadine hydrochloride or any fexofenadine hydrochloridehydrate or lower alcohol solvate. The use of other solvates, such as theethyl acetate solvate of the present invention, is not believed tointerfere with the effectiveness of the process. The startingfexofenadine hydrochloride can also be in an amorphous or anycrystalline crystal form. The process can be used as a purificationmethod by using the desired form in an unacceptably pure state asstarting material. The processes of the present invention can also bepracticed as the last step in the methods discussed in U.S. Pat. Nos.5,578,610, 5,589,487, 5,581,011, 5,663,412, 5,750,703, 5,994,549,5,618,940, 5,631,375, 5,644,061, 5,650,516, 5,652,370, 5,654,433,5,663,353, 5,675,009, 5,375,693 and 6,147,216 to prepare a novelpolymorph of the present invention.

Many processes of the present invention involve crystallization out of aparticular solvent. One skilled in the art would appreciate that theconditions concerning crystallization can be modified without affectingthe form of the polymorph obtained. For example, when mixingfexofenadine hydrochloride or free base in a solvent to form a solution,warming of the mixture can be necessary to completely dissolve thestarting material. If warming does not clarify the mixture, the mixturecan be diluted or filtered. To filter, the hot mixture can be passedthrough paper, glass fiber or other membrane material, or a clarifyingagent such as celite. Depending upon the equipment used and theconcentration and temperature of the solution, the filtration apparatusmay need to be preheated to avoid premature crystallization.

The conditions can also be changed to induce precipitation. A preferredway of inducing precipitation is to reduce the solubility of thesolvent. The solubility of the solvent can be reduced, for example, bycooling the solvent.

In one embodiment, an anti-solvent is added to a solution to decreaseits solubility for a particular compound, thus resulting inprecipitation. In another embodiment, an anti-solvent is added to anoily residue or a gummy material, wherein the low solubility of theanti-solvent for a particular compound results in precipitation of thatcompound.

Another manner to accelerate crystallization is by seeding with acrystal of the product or scratching the inner surface of thecrystallization vessel with a glass rod. Other times, crystallizationcan occur spontaneously without any inducement. The present inventionencompasses both embodiments where precipitation happens spontaneouslyor is induced, unless if such inducement is critical for obtaining aparticular polymorphic form of fexofenadine hydrochloride.

As an antihistamine, fexofenadine is effective at relieving symptomscaused by airborne and contact inducers of histamine release. Suchsubstances include pollen, spores, animal dander, cockroach dander,industrial chemicals, dust and dust mites. Symptoms that can bealleviated by fexofenadine include bronchial spasms, sneezing,rhinorrhia, nasal congestion, lacrimation, redness, rash, urticaria anditch.

Fexofenadine hydrochloride Forms XVI useful for delivering fexofenadineto the gastrointestinal tract, mucus membranes, bloodstream and inflamedtissues of a patient suffering from inflammation caused by a histamine.They can be formulated into a variety of compositions for administrationto humans and animals.

Pharmaceutical compositions of the present invention containfexofenadine hydrochloride Form XVI, optionally in a mixture with otherforms or amorphous fexofenadine and/or active ingredients such aspseudoephedrine. They can also be optionally mixed with pseudoephedrine.In addition to the active ingredient(s), the pharmaceutical compositionsof the present invention can contain one or more excipients. Excipientsare added to the composition for a variety of purposes.

Diluents increase the bulk of a solid pharmaceutical composition and canmake a pharmaceutical dosage form containing the composition easier forthe patient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelitinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet can include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flowability of non-compacted solidcomposition and improve the accuracy of dosing. Excipients that canfunction as glidants include colloidal silicon dixoide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from a punch anddye. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punch and dye, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce adhesion and ease release of the product formthe dye. Lubricants include magnesium stearate, calcium stearate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,fexofenadine hydrochloride Form XVI and any other solid excipients aredissolved or suspended in a liquid carrier such as water, vegetable oil,alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the present invention can also containa buffer such as guconic acid, lactic acid, citric acid or acetic acid,sodium guconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts to use can be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable route in any given case willdepend on the nature and severity of the condition being treated, themost preferred route of the present invention is oral. The dosages canbe conveniently presented in unit dosage form and prepared by any of themethods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges as well as liquid syrups,suspensions and elixirs.

A dosage form of the present invention is a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell can be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients can be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filing can be prepared by wetgranulation. In wet granulation some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, which causes the powders to clumpup into granules. The granulate is screened and/or milled, dried andthen screened and/or milled to the desired particle size. The granulatecan then be tableted or other excipients can be added prior totableting, such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For instance, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can be compressed subsequently into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well-suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in particularformulation challenges of direct compression tableting.

A capsule filling of the present invention can comprise any of theaforementioned blends and granulates that were described with referenceto tableting, only they are not subjected to a final tableting step.

Capsules, tablets and lozenges and other unit dosage forms preferablycontain a dosage level of about 30 to about 180 mg of fexofenadinehydrochloride. Other dosages may also be administered depending on theneed.

The following describes the instrumentation used by the presentinvention to characterize the new polymorphs. The PXRD patterns (such asthat for fexofenadine HCl Form XVI) were obtained by methods known inthe art using a Scintag X-ray powder diffractometer, a variablegoniometer, an X-Ray tube with Cu target anode (Cu radiation λ=1.5418 Å)and a solid state detector. A round standard aluminum sample holder witha round zero background quartz plate was used. Scans were performed overa range of 2 to 40 degrees two-theta, continuously, with a scan rate of3 degrees/min.

The DSC thermogram was obtained using a DSC Mettler 821 Star. Thetemperature range of scans was 30-350° C. at a rate of 10° C./min. Theweight of the sample was 2-5 mg. The sample was purged with nitrogen gasat a flow rate of 40 mL/min. Standard 40 Φl aluminum crucibles havinglids with three small holes were used.

The TGA thermogram for fexofenadine hydrochloride Form XVI was performedon Mettler TG50 using standard alumina pan and a sample weight: 7-15 mg.

EXAMPLES Example 1 Preparation of Fexofenadine Hydrochloride Form XVI

HCl/IPA (1.6 ml) (6.05-6.24 N) was added to methanol (20 ml) and wascooled in an ice water bath. This solution was added to fexofenadinefree base (5 grams) in a round bottom flask with a magnetic stirrer inan ice bath. The fexofenadine base dissolved immediately. The solutionwas filtered thru a glass fiber filter (GF/F), and the solventevaporated off in a water bath at a temperature of 25° C. using a wateraspirator, followed by a diaphragm pump, which was followed by an oilpump. Heptane (15 ml) was added. The stirrer was turned on, 5 ml ofmethanol was added and the slurry was stirred overnight. The next day itwas filtered and dried in the vacuum oven for 2 hours at 65° C. PXRDanalysis confirmed presence of Form XVI of fexofenadine hydrochloride.

KF=6.685% Elemental analysis: C: 66.28% H: 7-89% Cl: 5.65%

Example 2 Preparation of Fexofenadine Hydrochloride Form XVI

Example 1 was repeated, except 4 ml of methanol was used in thecrystallization step instead of 5 ml. PXRD analysis confirmed presenceof Form XVI of fexofenadine hydrochloride.

KF=6.507% Elemental analysis: C: 66.80% H: 7.91% Cl: 6.23%

Example 3 Preparation of Fexofenadine Hydrochloride Form XVI

Example 1 was repeated, except 3 ml of methanol was used in thecrystallization step instead of 5 ml. PXRD analysis confirmed presenceof Form XVI of fexofenadine hydrochloride.

KF=6.221% Elemental analysis: C: 67.18% H: 7.74% Cl: 6.35%

Example 4 Preparation of Fexofenadine Hydrochloride Form XVI

Example 1 was repeated, except 2 ml of methanol was used in thecrystallization step instead of 5 ml. PXRD analysis confirmed presenceof Form XVI of fexofenadine hydrochloride.

KF=7.314% Elemental analysis: C: 65.95% H: 7.77% Cl: 6.34%

Example 5 Preparation of Fexofenadine Hydrochloride Form XVI

Example 1 was repeated, except 2.5 ml of methanol was used in thecrystallization step instead of 5 ml. PXRD analysis confirmed presenceof Form XVI of fexofenadine hydrochloride.

KF=6.250% Elemental analysis: C: 66.70% H: 7.64% Cl: 6.40%

Example 6 Preparation of Fexofenadine Hydrochloride Form XVI

Fexofenadine free base (20 grams) was crushed and put into a 250 mlround bottom flask in an ice bath with a magnetic stirrer. HCl/IPA (6.5ml) was added to 80 ml methanol and cooled in an ice bath, and thenadded to the flask with mixing. After 15 minutes, the flask wasfiltered, and the filtrate evaporated off at room temperature first witha water aspirator then with a diaphragm pump and finally with an oilpump. The remaining material (5 grams) was stirred as a slurry overnightwith a mixture of heptane (15 ml) and methanol (1.5 ml), filtered anddried for 1 hour at 65° C. under vacuum. PXRD analysis confirmedpresence of Form XVI of fexofenadine hydrochloride.

Example 7 Process for Preparation of Fexofenadine-HCl Form XVI byCrystallization from Methanol

Step 1: Preparation of HCl Gas Solution in Methanol

HCl gas was dissolved in cold methanol (T<10° C.), until about 5% w/wconcentration was achieved.

Step 2: Dilution of HCl/Methanol Solution

Methanol/HCl solution (79.9 grams) (4.5 w/w) was diluted with 121.8grams of methanol to obtain diluted HCl/methanol solution.

Step 3: Titration of Fexofenadine-Base with Diluted HCl/MethanolSolution

The diluted HCl/methanol solution was cooled (T<10° C.). Fexofendinebase (50 grams) (1.88% H₂O) was reacted with the diluted HCl/methanolsolution, to form a fexofenadine-HCl solution. The molar ratio betweenfexofenadine-base and HCl was 1:1.

Step 4: Removal of Particulate Matter

The fexofenadine-HCl solution was filtered under reduced pressure toremove particulate matter (foreign particles).

Alternative A—Step 5: Isolation of the Product

The clear solution was distilled under reduced pressure at a jackettemperature of not more than 40° C. until the ratio of the residualsolvent in the reactor was 2 to 2.5 volumes vs. the weight offexofenadine base (ml/g).

After the final solvent volume was reached, the solution was seeded withfexofenadine HCl Form XVI crystals, and then stirred for an additional30 to 90 minutes. The seeded solution was cooled and kept at atemperature of 0 to 10° C. for at least 4 hours, and the slurry wasstirred for an additional 30 to 90 minutes. The solid was separated fromthe mother liquor by filtration under reduced pressure. The wet productwas dried under reduce pressure at a temperature of 50-65° C.

Alternative B—Step 5: Isolation of the Product

The clear solution was distilled under reduced pressure at a jackettemperature not more than 40° C. until there was no more distillate.Methanol in the ratio of 2 to 2.5 volumes vs. the weight of fexofenadinebase was added to the reactor (ml/g), and the fexofenadine HCl inmethanol mixture was heated to dissolution.

After the final solvent volume was reached, the solution was seeded withfexofenadine HCl Form XVI crystals, and then stirred for an additional30 to 90 minutes. The seeded solution was cooled and kept at atemperature of 0 to 10° C. for at least 4 hours, and the slurry wasstirred for an additional 30 to 90 minutes. The solid was separated fromthe mother liquor by filtration under reduced pressure. The wet productwas dried under reduce pressure at a temperature of 50-65° C.

Example 8 Preparation of Fexofenadine Hydrochloride Form XVI fromAmorphous Form

Amorphous fexofenadine HCl (5 gr) was stirred in a mixture of heptane(15 ml) and methanol (1.5 ml) at room temperature. After stirringovernight, a solid was filtered and dried at 65° C. The PXRD pattern ofthe solid confirmed that the product was fexofenadine hydrochloride FormXVI.

Having thus described the invention with reference to particularpreferred embodiments and illustrated it with examples, those in the artwill appreciate modifications to the invention as described andillustrated that do not depart from the spirit and scope of theinvention as disclosed in the specification. All the references citedherein are incorporated by reference in their entirety.

1-10. (canceled)
 11. The A pharmaceutical formulation comprising aneffective amount of crystalline fexofenadine hydrochloride hydratehaving a PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1±0.2degrees two theta, a pharmaceutically acceptable excipient andpseudoephedrine hydrochloride.
 12. A method of inhibiting bindingbetween an H₁ receptor and histamine in a patient suffering fromcontraction of the bronchi, vasodilation, itching or other inflammationresponses to histamine comprising administering to the patient apharmaceutical formulation comprising an effective amount of crystallinefexofenadine hydrochloride hydrate having a PXRD pattern with peaks at10.1, 15.2, 18.6, 19.2, 20.1±0.2 degrees two theta, and apharmaceutically acceptable excipient. 13-54. (canceled)